Davidson Fellows - 2012 Laureate Manoj Kanagaraj

Age: 18Chino Hills, CACategory: ScienceProject Title: “A Novel Mechanism for HER2 Targeted Drug Resistance: The Role of t-DARPP in a Compensatory Signaling Shift Between the EGFR and HER2 Pathways.”

Approximately 25% of breast cancer tumor cells overexpress the human epidermal growth factor receptor 2 (HER2) due to a gene mutation. These HER2+ breast cancers tend to be more aggressive than other types of breast cancers. As a result, many drugs have been developed to specifically target HER2, such as trastuzumab (Herceptin). Still, approximately 50-70% of HER2+ breast cancer tumors become resistant to trastuzumab within a year. Previous reports have shown that a protein called t-DARPP may play a role in this resistance mechanism.

Manoj developed a new model by which t-DARPP confers this resistance – by activating an alternate signaling pathway through EGFR when HER2 is inhibited to sustain tumor cell survival. Through this study, he found that t-DARPP expression led to increased EGFR activity and resistance to HER2 targeted therapies. These results suggest that t-DARPP plays a role in activating alternate HER receptors and shifting signaling from HER2 to EGFR to confer resistance to HER2 targeted drugs. These findings are significant because the development of an effective combination strategy to overcome this resistance mechanism would have implications not only in breast cancer treatment, but also in potentially any cancer that overexpresses HER2 or t-DARPP.

Breast cancer is the second leading cause of cancer death among women, nearly 230,000 cases of this disease are diagnosed each year in the United States alone. Manoj’s research only deals with a subset of breast cancer patients: those who are HER2+. However, drug resistance in all types of cancer treatment is a serious problem in clinical therapies. Consequently, if a solution is developed in the future to resolve the resistance mechanism he identified, such as a combination of drugs or an entirely new drug, then his work could potentially have an impact on improving the quality of life for these breast cancer patients.

Manoj was a Siemens Math, Science and Technology Competition Finalist and a National Merit Scholar. Attending Duke University this fall, he plans to major in biology and possibly global health to earn a MD and PhD to become a physician scientist.